The present invention relates to novel chemical compounds, pharmacological uses and compositions therefor. Particularly, the present novel invention relates to analogs of lipoxin B (LX-B) or 5D,14,15-trihydroxy-6,8,10,12-eicosatetraenoic acid and uses therefor. Also, the present invention relates to novel methods and intermediates for the synthesis of LX-B compounds.
Arachidonic acid plays a central role in a complex system of biological controls wherein oxygenated derivatives of a arachidonic acid, such as prostaglandins, thromboxanes, and leukotrienes are mediators. Each of these classes of compounds are metabolites of arachidonic acid and include, for example, PGF.sub.2 .alpha., prostacyclin or PGI.sub.2, and thromboxane A.sub.2. Each of these substances are formed from arachidonic acid through prostaglandin endoperoxide precursors, i.e., PGG.sub.2 and PGH.sub.2, through the action of a cyclooxygenase enzyme on the arachidonic acid substrate.
In contrast to the cyclopentane-containing prostaglandins and thromboxanes, the leukotrienes are acyclic arachidonic acid metabolites which are formed by transformation of arachidonic acid into an unstable epoxide intermediate, leukotriene A.sub.4, which can be converted enzymatically by hydration to leukotriene B.sub.4 and by addition of glutathione to leukotriene C.sub.4. Leukotriene C.sub.4 is metabolized to leukotriene D.sub.4 and leukotriene E.sub.4 by successive elimination of a gamma-glutamyl residue and glycine.
The aforementioned leukotrienes are known in the art as mediators of immediate hypersensitivity reactions and inflammation. In particular, the slow-reacting substance of anaphylaxis (SRS-A) consists of leukotrienes C.sub.4, D.sub.4 and E.sub.4. The cysteinyl-containing leukotrienes are also potent bronchoconstrictors, increase vascular permeability in post-capillary venules, and stimulate mucus secretion. Leukotriene B.sub.4 causes adhesion and chemotactic movement of leukocytes and stimulates aggregation, enzyme release, and the generation of superoxide in neutrophils. Leukotriene C.sub.4, D.sub.4 and E.sub.4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, play a pathophysiological role in immediate hypersensitivity reactions. As such, these leukotrienes, as well as leukotriene B.sub.4, have marked pro-inflammatory effects.
The first series of leukotrienes were discovered from products, e.g., 5-hydroperoxyeicosatetraenoic acid (5-HPETE), derived enzymatically from arachidonic acid through the action of a 5-lypoxygenase enzyme. For discussion of the various leukotriene metabolites of 5-HPETE, their formation and biological effects, see Bengt Samuelsson, "Leukotrienes: Mediators of immediate hypersensitivity reactions in inflammation," Science 220:568-575 (1983).
These originally discovered leukotrienes were all characterized by the initial introduction of an oxygen atom at the C-5 position. However, other enzymatic pathways were subsequently identified wherein lipoxygenase enzymes catalyze the introduction of oxygen atom at other positions besides C-5. Particularly known are leukotrienes formed with initial oxygenation at either C-12 or C-15 through 12- or 15-lipoxygenases. For example, a 15-lipoxygenase converts arachidonic acid to 15-hydroperoxy-eicosatetraenoic acid (15-HPETE). This compound is then further metabolized to 14,15-dihydroxy-5,8,10,12-eicosatetraenoic acid (14,15-diHETE) as well as 8,15-dihydroxy-5-cis-9,11,13-trans-eicosatetraenoic acids.
The present disclosure provides analogs of one series of a new family of oxygenated derivatives of arachidonic acid which arise through interactions of multiple distinct lipoxygenase pathways and therefore are given the name "lipoxins", or LX compounds. These novel lipoxins are, like the leukotrienes, oxygenated derivatives of arachidonic acid. They contain, however, a trihydroxy-tetraene structure instead of the characteristic triene structure of the leukotrienes.
Neutrophils are leukocytes which mediate inflammatory processes in mammals. They aggregate, degranulate, generate active oxygen species, and release oxidation products of arachidonate when exposed to appropriate stimuli (See G. Weissman et al. (1980) N. Engl. J. Med. 303:27-34 and C. W. Serhan et al. (1980) J. Immunol. 125:2020-2024). Upon activation, human neutrophils release arachidonic acid from membrane phospholipids which may be oxygenated by either cyclooxygenase (prostaglandins, prostacyclin, or thromboxane) or lipoxygenase (leukotriene) pathways. For example, activation of the 5-lipoxygenase pathway leads to the formation of LTB.sub.4 and its isomers, as indicated above. The fact that LTB.sub.4 is a potent chemo-attractant and is the agent which stimulates secretion in human neutrophils (See R. A. Lewis et al. (1981) J. Exp. Med. 154:1243-1248 and C. N. Serhan et al. (1982) Biochem. Biophys. Res. Commun. 107:1006-1012) indicates that activation of the 5-lipoxygenase pathway plays a key role in the inflammatory response in mammals.
In addition to pro-inflammatory effects associated with the 5-lipoxygenase pathway, human leukocytes are also capable of oxygenating arachidonate by means of the 15-lipoxygenase pathway as indicated above. See U. Lundberg et al. (1981) FEBS Lett. 126:127-132; W. Jubiz et al. (1981) Biochem. Biophys. Res. Commun. 99:976-986; and O. Radmark et al. (1982) In: Advances in Prostaglandin, Thromboxane and Leukotriene Research (eds. B. Samuelsson, P. Ramwell and R. Paoletti), vol. 11, Raven Press, NY, pp. 61-70. Initial oxygenation at C-15 leads to the formation of 15-hydroperoxyeicosatetraenoic acid (15-HPETE) which may be further transformed to 14,15- or 8,15-hydroperoxyeicosatetraenoic acids, as indicated above. See U. Lundberg et al. (1981) FEBS Lett. 126:127-132; W. Jubiz et al. (1981) Biochem. Biophys. Res. Commun. 99:976-986; O. Radmark et al. (1982) In: Advances in Prostaglandin, Thromboxane and Leukotriene Research (eds. B. Samuelsson, P. Ramwell and R. Paoletti), vol. 11, Raven Press, NY, pp. 61-70; and R. L. Maas et al. (1981) Proc. Natl. Acad. Sci. 78:5523-5527. A biological role for the 15-lipoxygenase pathway and its metabolites has not heretofore been elucidated. Recent studies indicate that 15-HPETE inhibits the release of arachidonate from platelets (see M. Lagarde et al. (1981) Biochem. Biophys. Res. Commun. 99:1398-1402) and that 15-HETE, a metabolic product of 15-HPETE, inhibits not only the 12-lipoxygenase but also leukotriene biosynthesis (see J. Y. Vanderhoek et al. (1980) J. Biol. Chem. 255:5996-5998 and J. Y. Vanderhoek et al. (1980) J. Biol. Chem. 255:10064-10065).